2-aminomethyl benzimidazole derivatives

ABSTRACT

Compounds having the formula ##EQU1## WHEREIN Ar is phenyl optionally substituted by one or more halogens, alkyl having 1 to 4 carbons or alkoxy containing up to 4 carbons, and R 1  and R 2  each is alkyl having one to 4 carbons or ##EQU2## is piperidino, pyrrolidino, morpholino and hexamethyleneimino. The compounds are prepared by reacting the corresponding 2-chloromethyl benzimidazole with ##EQU3## The compounds possess analgesic, antihypertensive, gastric antisecretory, antiinflammatory, antibronchoconstrictive, anticholinergic, spasmolytic, sedative, antiulcerous, vasodilatatory, central nervous system stimulant, antiarythmic, diuretic and antihistaminic properties.

The present invention relates to novel derivatives of 2-aminomethylbenzimidazole, their process of preparation and their therapeuticapplication.

The novel compounds according to the present invention correspond to thegeneral formula: ##EQU4## in which: Ar represents a phenyl ringoptionally substituted by one or more halogen atoms, by one or morealkyl radicals containing from 1 to 4 carbon atoms or by one or morealkoxy groups which each contain up to 4 carbon atoms; and

R₁ and R₂ each represent an alkyl radical containing from 1 to 4 carbonatoms, or form together with the nitrogen atom to which they areattached, a heterocyclic radical selected from piperidino, pyrrolidino,morpholino and hexamethyleneimino.

The process according to the present invention comprises condensing aderivative of 2-chloromethyl benzimidazole of the general formula:##EQU5## with an amine of the general formula: ##EQU6## in which thesymbols, R₁, R₂ and Ar have the same significance as in formula (I).

The derivatives of formula (II) are themselves obtained by the reactionof a derivative of 2-hydroxymethyl benzimidazole of the general formula:##EQU7## in which Ar has the same significance as in formula (I), withthionyl chloride of formula:

    SOCl.sub.2                                                 (V)

the derivatives of formula (IV) resulting from the reaction, in ahydroalcoholic medium maintained under reflux, of the hydrochloride of aderivative of piperidinomethylacetophenone of the general formula:##EQU8## in which Ar has the same significance as in formula (I), with2-methanol benzimidazole of formula:

The following preparations are given by way of example to illustrate thepresent invention.

EXAMPLE 1 1-(2'-benzoylethyl)-2-dimethylaminomethyl benzimidazole (CodeNo: 72 522)

1st stage: 1-(benzoylethyl)-2-hydroxymethyl benzimidazole (Code No: 72337)

A mixture of 0.06 mol of 2-hydroxymethyl benzimidazole, 0.06 mol ofpiperidinomethyl acetophenone hydrochloride, 48 ml. of methanol and 72ml of water is maintained under reflux for 2 hours. After cooling toambient temperature, the desired compound precipitates out, is filteredand recrystallised from 30 ml. of ethanol.

Melting point = 149°C

Yield = 66%

Empirical formula = C₁₇ H₁₆ N₂ O₂

    Elementary analysis:                                                                   C          H       N                                                 ______________________________________                                        Calculated %                                                                             72.84        5.75    9.99                                          Found %    72.68        5.85    10.00                                         ______________________________________                                    

2nd stage: 1-(2' -benzoylethyl)-2-chloromethyl benzimidazole (Code No:72 370)

A solution of 0.95 mol of thionyl chloride in 270 c.c. of chloroform isadded, at 15°C over a period of 1 hour, to a suspension of 0.62 mol of1-(2'-benzoylethyl)-2-methanol benzimidazole in 480 c.c. of chloroform.After contact for 2 hours at ambient temperature, the excess thionylchloride is evaporated and the methanolic solution of hydrochloride isneutralised with sodium bicarbonate. After filtration and evaporation,the crude base is recrystallised from ethyl acetate.

Melting point = 109°C

Yield = 67%

Empirical formula = C₁₇ H₁₅ ClN₂ O

    Elementary analysis:                                                                   C          H       N                                                 ______________________________________                                        Calculated %                                                                             68.34        5.06    9.38                                          Found %    68.14        5.18    9.24                                          ______________________________________                                    

3rd stage: 1-(2'-benzoylethyl)-2-dimethylaminomethyl benzimidazole (CodeNo. 72 522)

0.13 mol of 1-(2'-benzoylethyl)-2-chloromethyl benzimidazole obtainedfrom the preceding stage and 0.26 mol of dimethylamine are dissolved in300 c.c. of benzene.

The solution is maintained at 50°C for 3 hours. After cooling thedimethylamine hydrochloride formed is filtered off, and the benzene isevaporated. The base is crystallised from petroleum ether.

Melting point = 90°C

Yield = 70%

Empirical formula = C₁₉ H₂₁ N₃ O

    Elementary analysis:                                                                   C          H       N                                                 ______________________________________                                        Calculated %                                                                             74.24        6.89    13.67                                         Found %    74.18        6.87    13.52                                         ______________________________________                                    

EXAMPLE 2 1-(2'-benzoylethyl maleate)-2-diethylaminomethyl benzimidazole(Code No. 72 573)

0.1 mol. of 1-(2'-benzolyethyl)-2-chloromethyl benzimidazole obtained bythe procedure of stage 2 according to Example 1, and 0.2 mol. ofdiethylamine are dissolved in 300 c.c. of benzene.

The solution is maintained at 40°C for 3 hours. After filtration of thediethylamine hydrochloride formed, the benzene is evaporated off. Thecrude base is salified in 200 c.c. of acetone with the aid of 0.1 mol.of maleic acid.

Melting point = 108°C

Yield = 43%

Empirical formula = C₂₅ H₂₉ N₃ O₅

    Elementary analysis:                                                                   C          H       N                                                 ______________________________________                                        Calculated %                                                                             66.50        6.47    9.31                                          Found %    66.50        6.55    9.51                                          ______________________________________                                    

The compounds listed in the following Table I have been prepared by themethod of operation of the first stage according to Example 1, whilstthe compounds listed in Table II have been prepared by the method ofoperation of stage 3 according to Example 1 or by the method ofoperation of Example 2, following the synthesis of the crude base, orits salt.

                                      TABLE I                                     __________________________________________________________________________                                    O                                                                             ∥                                                                    --CH.sub.2 --CH.sub.2 --C--Ar(II)                                               Melting  Elementary Analysis                Code                 Empirical                                                                            Molecular                                                                           point                                                                              Yield                                                                             Calculated %                                                                            Found %                  No.  Ar.             Formula                                                                              Weight                                                                              (°C)                                                                        %   C   H  N  C   H  N                 __________________________________________________________________________    72316                C.sub.17 H.sub.14 Cl.sub.2 N.sub.2 O                                                 333.21                                                                              130  80  61.27                                                                             4.24                                                                             8.41                                                                             61.03                                                                             4.28                                                                             8.21              72336                C.sub.17 H.sub.14 ClFN.sub.2 O                                                       316.75                                                                              118  42  64.46                                                                             4.46                                                                             8.84                                                                             64.20                                                                             4.46                                                                             8.70              72411                C.sub.21 H.sub.23 ClN.sub.2 O.sub.2                                                  370.87                                                                               80  58  68.01                                                                             6.25                                                                             7.55                                                                             68.00                                                                             6.27                                                                             7.47              72294                C.sub.18 H.sub.17 ClN.sub.2 O                                                        312.78                                                                              139  51  69.11                                                                             5.48                                                                             8.96                                                                             69.03                                                                             5.60                                                                             8.85              72335                C.sub.19 H.sub.19 ClN.sub.2 O                                                        326.81                                                                               90  57  69.82                                                                             5.86                                                                             8.57                                                                             69.99                                                                             5.85                                                                             8.43              72346                C.sub.19 H.sub. 19 ClN.sub.2 O.sub.                                                  358.81                                                                              138  60  63.60                                                                             5.34                                                                             7.81                                                                             63.45                                                                             5.57                                                                             7.61              72379                C.sub.20 H.sub.21 ClN.sub.2 O.sub.                                                   388.84                                                                              135  50  61.77                                                                             5.44                                                                             7.21                                                                             61.97                                                                             5.39                                                                             7.07              __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________                   O                                                                             ∥                                                                    --CH.sub.2 --CH.sub.2 --C--Ar(I)                               Code          R          Empirical                                                                             Mole-                                                                              Melt-                                                                             Yield                                                                             Elementary Analysis             No. Ar.       --N∠                                                                          Form Formula cular                                                                              ing (%)       C   H  N                                R.sub.2            weight                                                                             point                                                                         (°C)                             __________________________________________________________________________                                                  %                               72493               base C.sub.21 H.sub.23 N.sub.3 O                                                           333.42                                                                              97 74  Calculated                                                                          75.64                                                                             6.95                                                                             12.60                                                            Found 75.79                                                                             7.04                                                                             12.41              72491               base C.sub.22 H.sub.25 N.sub.3 O                                                           347.44                                                                             136 53  Calculated                                                                          76.05                                                                             7.25                                                                             12.10                                                            Found 75.98                                                                             7.28                                                                             12.13              72494         --NO  base C.sub.21 H.sub.23 N.sub.3 O.sub.2                                                     349.42                                                                             111 71  Calculated                                                                          72.18                                                                             6.64                                                                             6.57                                                             Found 72.00                                                                             6.57                                                                             12.07              72451               base C.sub.23 H.sub.27 N.sub.3 O                                                           358.45                                                                             110 58  Calculated                                                                          76.42                                                                             7.53                                                                             11.63                                                            Found 76.23                                                                             7.58                                                                             11.83              72479         N(CH.sub.3).sub.2                                                                   base C.sub.19 H.sub.20 ClN.sub.3 O                                                         341.83                                                                             123 65  Calculated                                                                          66.76                                                                             5.90                                                                             12.29                                                            Found 66.76                                                                             5.75                                                                             12.12              72390         N(C.sub.2 H.sub.5).sub.2                                                            base C.sub.21 H.sub.24 ClN.sub.3 O                                                         369.88                                                                             111 67  Calculated                                                                          68.19                                                                             6.54                                                                             11.36                                                            Found 68.36                                                                             6.65                                                                             11.43                                                            %                               72366               base C.sub.21 H.sub.22 ClN.sub.3 O                                                         367.87                                                                             135 73  Calculated                                                                          68.56                                                                             6.03                                                                             11.42                                                            Found 68.57                                                                             6.16                                                                             11.47              72389               base C.sub.22 H.sub.24 ClN.sub.3 O                                                         381.89                                                                             156 57  Calculated                                                                          69.19                                                                             6.33                                                                             11.00                                                            Found 68.99                                                                             6.26                                                                             11.01              72359         --NO  base C.sub.21 H.sub.22 ClN.sub.3 O.sub.                                                    383.87                                                                             131 78  Calculated                                                                          65.70                                                                             5.78                                                                             10.95                                                            Found 65.63                                                                             5.77                                                                             10.80              72418               base C.sub.23 H.sub.26 ClN.sub.3 O                                                         395.92                                                                             121 30  Calculated                                                                          69.77                                                                             6.62                                                                             10.61                                                            Found 69.83                                                                             6.44                                                                             10.49              72663         --N(CH.sub. 3).sub.2                                                                maleate                                                                            C.sub.23 H.sub.24 FN.sub.3 O.sub.5                                                    441.45                                                                             152 50  Calculated                                                                          62.57                                                                             5.48                                                                             9.52                                                             Found 62.44                                                                             5.58                                                                             9.57               72568         --N(C.sub. 2 H.sub.5).sub.2                                                         maleate                                                                            C.sub.25 H.sub.28 FN.sub.3 O.sub.                                                     469.50                                                                             130 32  Calculated                                                                          63.95                                                                             6.01                                                                             8.95                                                             Found 63.75                                                                             6.08                                                                             8.83               72708               base C.sub.21 H.sub.22 FN.sub. 3 O                                                         351.41                                                                              81 77  Calculated                                                                          71.77                                                                             6.31                                                                             11.96                                                            Found 71.80                                                                             6.46                                                                             11.84              72487               base C.sub.22 H.sub.24 FN.sub.3 O                                                          365.44                                                                             114 71  Calculated                                                                          72.30                                                                             6.62                                                                             11.50                                                            Found 72.28                                                                             6.68                                                                             11.47              72526         --NO  maleate                                                                            C.sub.25 H.sub.26 FN.sub.3 O.sub.6                                                    483.48                                                                             135 61  Calculated                                                                          62.10                                                                             5.42                                                                             8.69                                                             Found 62.20                                                                             5.43                                                                             8.88               72488               base C.sub.23 H.sub.26 FN.sub.3 O                                                          379.46                                                                             104 68  Calculated                                                                          72.80                                                                             6.91                                                                             11.07                                                            Found 72.79                                                                             7.03                                                                             10.98              72524         --N(CH.sub.3).sub.2                                                                 base C.sub.23 H.sub.29 N.sub. 3 O.sub.2                                                    379.49                                                                              84 86  Calculated                                                                          72.79                                                                             7.70                                                                             11.07                                                            Found 72.68                                                                             7.63                                                                             10.94              72727         --N(C.sub.2 H.sub.5).sub.2                                                          base C.sub.25 H.sub.33 N.sub.3 O.sub.                                                      407.54                                                                              84 50  Calculated                                                                          73.67                                                                             8.16                                                                             10.31                                                            Found 73.46                                                                             8.16                                                                             10.23              72465               base C.sub.25 H.sub.31 N.sub.3 O.sub.                                                      405.52                                                                             113 69  Calculated                                                                          74.04                                                                             7.71                                                                             10.36                                                            Found 74.14                                                                             7.73                                                                             10.52              72464               base C.sub.26 H.sub.33 N.sub.3 O.sub.2                                                     419.55                                                                             130 73  Calculated                                                                          74.43                                                                             7.93                                                                             10.02                                                            Found 74.23                                                                             7.80                                                                             10.19                                                            %                               72523         --NO  base C.sub.25 H.sub.31 N.sub.3 O.sub.                                                      421.52                                                                             127 72  Calculated                                                                          71.23                                                                             7.41                                                                             9.97                                                             Found 71.15                                                                             7.27                                                                             10.11              72463               base C.sub.27 H.sub.35 N.sub.3 O.sub.2                                                     433.57                                                                             100 60  Calculated                                                                          74.79                                                                             8.14                                                                             9.69                                                             Found 74.94                                                                             8.25                                                                             9.89               72457         --N(CH.sub.3).sub.2                                                                 base C.sub.20 H.sub.23 N.sub.3 O                                                           321.41                                                                             106 75  Calculated                                                                          74.73                                                                             7.21                                                                             13.07                                                            Found 74.82                                                                             7.21                                                                             12.87              72574         --N(C.sub. 2 H.sub.5).sub.2                                                         maleate                                                                            C.sub.26 H.sub.31 N.sub.3 O.sub.5                                                     465.53                                                                              99 55  Calculated                                                                          67.08                                                                             6.71                                                                             9.03                                                             Found 66.90                                                                             6.81                                                                             9.03               72476               base C.sub.22 H.sub.25 N.sub.3 O                                                           347.44                                                                             122 63  Calculated                                                                          76.05                                                                             7.25                                                                             12.10                                                            Found 75.89                                                                             7.14                                                                             12.03              72477               base C.sub.23 H.sub.27 N.sub.3 O                                                           361.47                                                                             155 82  Calculated                                                                          76.42                                                                             7.53                                                                             11.63                                                            Found 76.21                                                                             7.33                                                                             11.44              72478         --NO  base C.sub.22 H.sub.25 N.sub.3 O.sub.                                                      363.44                                                                             135 70  Calculated                                                                          72.70                                                                             6.93                                                                             11.56                                                            Found 72.70                                                                             6.79                                                                             11.50                                                            %                               72483               base C.sub.24 H.sub.29 N.sub. 3 O                                                          375.50                                                                              99 56  Calculated                                                                          76.76                                                                             7.78                                                                             11.19                                                            Found 76.61                                                                             7.85                                                                             11.13              72712         --N(CH.sub.3).sub.2                                                                 base C.sub.21 H.sub.25 N.sub.3 O                                                           335.43                                                                             135 54  Calculated                                                                          75.19                                                                             7.51                                                                             12.53                                                            Found 75.24                                                                             7.50                                                                             12.44              72736         --N(C.sub.2 H.sub.5).sub.2                                                          maleate                                                                            C.sub.27 H.sub.33 N.sub.3 O.sub.5                                                     479.56                                                                             107 48  Calculated                                                                          67.62                                                                             6.94                                                                             8.76                                                             Found 67.65                                                                             7.00                                                                             8.68               72446               base C.sub.23 H.sub.27 N.sub.3 O                                                           361.47                                                                             118 63  Calculated                                                                          76.42                                                                             7.53                                                                             11.63                                                            Found 76.62                                                                             7.58                                                                             11.45              72540               base C.sub.24 H.sub.29 N.sub.3 O                                                           375.50                                                                             132 76  Calculated                                                                          76.76                                                                             7.78                                                                             11.19                                                            Found 76.86                                                                             7.79                                                                             11.27              72447         --NO  base C.sub.23 H.sub.27 N.sub.3 O.sub.                                                      377.47                                                                             116 53  Calculated                                                                          73.18                                                                             7.21                                                                             11.13                                                            Found 73.04                                                                             7.23                                                                             11.06                                       3/4                                                  72603               base C.sub.25 H.sub.31 N.sub.3 OH.sub.2 O                                                  403.04                                                                              72 46  Calculated                                                                          74.50                                                                             8.28                                                                             10.43                                                            Found 74.44                                                                             8.19                                                                             10.55                                                            %                               72490         --N(CH.sub.3).sub.2                                                                 base C.sub.21 H.sub.25 N.sub.3 O.sub.                                                      367.40                                                                              95 76  Calculated                                                                          68.64                                                                             6.86                                                                             11.44                                                            Found 68.67                                                                             6.88                                                                             11.24              72692         --N(C.sub.2 H.sub.5).sub.2                                                          maleate                                                                            C.sub.27 H.sub.33 N.sub.3 O.sub.7                                                     511.56                                                                             123 41  Calculated                                                                          63.39                                                                             6.50                                                                             8.21                                                             Found 63.19                                                                             6.54                                                                             8.26               72617               base C.sub.23 H.sub.27 N.sub. 3 O.sub.                                                     393.47                                                                              82 60  Calculated                                                                          70.20                                                                             6.92                                                                             10.68                                                            Found 70.00                                                                             7.01                                                                             10.58              72377               base C.sub.24 H.sub.29 N.sub.3 O.sub.3                                                     407.49                                                                             101 85  Calculated                                                                          70.73                                                                             7.17                                                                             10.31                                                            Found 70.93                                                                             7.29                                                                             10.19              72391         --NO  base C.sub.23 H.sub.27 N.sub.3 O.sub.                                                      409.47                                                                             150 65  Calculated                                                                          67.46                                                                             6.65                                                                             10.26                                                            Found 67.47                                                                             6.68                                                                             10.14              72398               base C.sub.25 H.sub.31 N.sub.3 O.sub.                                                      421.52                                                                             100 57  Calculated                                                                          71.23                                                                             7.41                                                                             9.97                                                             Found 71.04                                                                             7.47                                                                             9.81               72534         --N(CH.sub.3).sub.2                                                                 base C.sub.22 H.sub.27 N.sub.3 O.sub.4                                                     397.46                                                                             164 86  Calculated                                                                          64.48                                                                             6.85                                                                             10.57                                                            Found 66.26                                                                             6.87                                                                             10.51                                                            %                               72539         --N(C.sub.2 H.sub.5).sub.2                                                          base C.sub.24 H.sub.31 N.sub. 3 O.sub.4                                                    425.51                                                                             167 50  Calculated                                                                          67.74                                                                             7.34                                                                             9.88                                                             Found 67.91                                                                             7.28                                                                             9.97               72414               base C.sub.24 H.sub.29 N.sub.3 O.sub.                                                      423.50                                                                             154 71  Calculated                                                                          68.06                                                                             6.90                                                                             9.92                                                             Found 67.86                                                                             6.92                                                                             9.75               72413               base C.sub.25 H.sub.31 N.sub.3 O.sub.                                                      437.52                                                                             143 60  Calculated                                                                          68.63                                                                             7.14                                                                             9.61                                                             Found 68.43                                                                             7.06                                                                             9.45               72525         --N O maleate                                                                            C.sub.28 H.sub.33 N.sub.3 O.sub.9                                                     555.57                                                                             154 74  Calculated                                                                          60.53                                                                             5.99                                                                             7.56                                                             Found 60.72                                                                             5.89                                                                             7.63               72412               base C.sub.26 H.sub.33 N.sub.3 O.sub.                                                      451.55                                                                             136 55  Calculated                                                                          69.15                                                                             7.37                                                                             9.31                                                             Found 69.35                                                                             7.48                                                                             9.11               __________________________________________________________________________

The compounds of formula (I) have been tested on animals in thelaboratory and have been shown to possess analgesic, antihypertensive,gastric antisecretory, anti-inflammatory, antiobronochoconstrictive andanticholinergic, spasmolytic, sedative, antiulcerous, vasodilatatory,stimulants for the central nervous system, antiarythmic, diuretic andantihistaminic properties.

1. Analgesic properties

The compounds of formula (I), administered by oral means to the mouse,are capable of reducing the number of painful stretchings caused by theintraperitoneal injection of acetic acid.

By way of example, the following Table III lists the results obtained byadministration of 100 mg/Kg/p.o. of different compounds of formula (I).

                  TABLE III                                                       ______________________________________                                        Code No. of     Percentage reduction                                          compound tested of number of painful                                                          stretchings - (%)                                             ______________________________________                                        72 491          65                                                            72 523          45                                                            72 391          60                                                            72 617          70                                                            72 487          80                                                            72 663          60                                                            72 603          50                                                            72 708          60                                                            72 574          45                                                            ______________________________________                                    

2. Antihypertensive properties

The compounds of formula (I), administered by oral means to a ratsuffering from high blood pressure, are capable of lowering the systolicarteriel pressure.

By way of example, there is provided in the following Table IV theresults obtained by administration of different compounds of formula(I).

                  TABLE IV                                                        ______________________________________                                        Code No. of Dose administered                                                                           Percentage of                                       compound tested                                                                           (mg/Kg/p.o.)  rats with high                                                                blood pressure                                                                whose systolic                                                                arteriel pressure                                                             is returned to                                                                normal (%)                                          ______________________________________                                        72 491      200           50                                                  72 414      150           75                                                  72 525      200           50                                                  72 526      100           75                                                  72 568      200           50                                                  72 479      200           50                                                  72 457      200           50                                                  ______________________________________                                    

3. Gastric antisecretory properties

Administered by intraduodenal means to a rat, the compounds of formula(I) are capable of reducing the gastric secretion measured after Shayligature.

By way of example, the following Table V gives the results obtained byadministration of 50 mg/Kg/i.d. of different compounds of formula (I).

                  TABLE V                                                         ______________________________________                                        Code No. of   Percentage reductions in volume                                 compound tested                                                                             of gastric secretion - (%)                                      ______________________________________                                        72 493        25                                                              72 494        25                                                              72 523        25                                                              72 487        40                                                              ______________________________________                                    

4. Antiinflammatory properties

These properties are shown by a diminution of the local oedema caused bythe sub-plantar injection of a phlogogenic agent, such as carraghenin,in the rat following the oral administration of compounds of formula(I).

The following Table VI lists, by way of example, the percentagereduction of the oedems caused by the sub-plantar injection ofcarraghenin, resulting from the administration of 100 mg/Kg/p.o. ofdifferent compounds of formula (I).

                  TABLE VI                                                        ______________________________________                                        Code No. of    Percentage reduction of                                        compound tested                                                                              sub-plantar oedema                                                            (%)                                                            ______________________________________                                        72 494         40                                                             72 488         50                                                             72 526         55                                                             72 447         40                                                             72 366         60                                                             72 712         70                                                             72 390         60                                                             ______________________________________                                    

5. Antibronchoconstrictive and anticholinergic properties.

Injected by intraveinous or intraduodenal means, the compounds offormula (I) are capable of opposing the bronchoconstriction provoked inthe guinea-pig by the itraveinous injection of acetylcholine by theKonzett method.

By way of example, the following Table VII lists the results obtained bythe administration of different compounds of formula (I)

                  TABLE VII                                                       ______________________________________                                        Code No. of Dose         Percentage                                           compound tested                                                                           Administered inhibition of                                                                 bronchoconstriction                                                           (%)                                                  ______________________________________                                        72 573       5 mg/kg/i.v.                                                                              100                                                  72 412      100 mg/kg/i.d.                                                                             80                                                   72 414      100 mg/kg/i.d.                                                                             50                                                   72 525      100 mg/kg/i.d.                                                                             80                                                   72 534      100 mg/kg/i.d.                                                                             50                                                   72 391      100 mg/kg/i.d.                                                                             100                                                  72 398      100 mg/kg/i.d.                                                                             100                                                  72 487      100 mg/kg/i.d.                                                                             60                                                   72 526      100 mg/kg/i.d.                                                                             75                                                   72 447      100 mg/kg/i.d.                                                                             50                                                   72 540      100 mg/kg/i.d.                                                                             50                                                   72 603      100 mg/kg/i.d.                                                                             50                                                   72 708      100 mg/kg/i.d.                                                                             90                                                   72 457      100 mg/kg/i.d.                                                                             80                                                   72 736       10 mg/kg/i.v.                                                                             90                                                   72 727      100 mg/kg/i.d.                                                                             100                                                  ______________________________________                                    

6. Spasmolytic properties

The compounds of formula (I), introduced in the conserving medium arecapable of opposing the contractural action of barium chloride on theisolated duodenum of the rat. This activity is evaluated by takingpapaverine as standard.

Thus, the compounds of Code Nos. 72 573, 72 708, and 72 736 presents anequivalent spasmolytic actvity to that of papaverine.

7. Sedative properties

The compounds of formula (I), administered by oral means to the mouse,reduce the number of explorations in the escape enclosure.

By way of example, the following Table VIII lists the results obtainedby the administration of 100 mg/Kg/p.o. of different compounds offormula (I).

                  TABLE VIII                                                      ______________________________________                                        Code No. of   Percentage reduction of number                                  compound tested                                                                             of explorations in the escape                                                 enclosure                                                                     (%)                                                             ______________________________________                                        72 464        30                                                              72 377        30                                                              72 391        50                                                              72 663        30                                                              72 540        30                                                              72 603        30                                                              72 712        40                                                              72 692        30                                                              ______________________________________                                    

8. Antiulcerous properties

The compounds of formula (I) administered by intraduodenal means reducethe extent of gastric ulcers, provoked in a rat by tying of the pylorus(Shay ulcers).

By way of example, there is listed in the following Table IX, theresults obtained by the administrations of 50 mg/Kg/i.d. of differentcompounds of formula (I).

                  TABLE IX                                                        ______________________________________                                        Code No. of    Percentage reduction of                                        compound tested                                                                              Shay ulcers - (%)                                              ______________________________________                                        72 377         55                                                             72 398         25                                                             72 490         30                                                             72 488         25                                                             72 526         40                                                             72 447         35                                                             72 603         35                                                             72 359         35                                                             72 366         40                                                             72 712         55                                                             72 708         30                                                             72 390         40                                                             72 479         30                                                             72 457         30                                                             72 574         45                                                             72 736         30                                                             ______________________________________                                    

9. Vasodilatatory properties

The compounds of formula (I) are capable of augmenting the flow of thecoronary vessels of the isolated heart of a guinea-pig when saidcompounds are added in the perfusion liquid of said organ.

By way of example, there can be found in the following Table X, thepercentage augmentation of the flow of the isolated heart of aguinea-pig by adding different compounds of formula (I) to the perfusionliquid, in a concentration of 1 μg/ml.

                  TABLE X                                                         ______________________________________                                        Code No. of  Percentage augmentations of flow                                 compound tested                                                                            of isolated heart of a guinea-pig                                             (%)                                                              ______________________________________                                        72 490       140                                                              72 479       80                                                               72 478       50                                                               72 692       60                                                               ______________________________________                                    

10. Central nervous system stimulating properties

The compounds of formula (I), administered by oral means to the mouse,provoke an augmentation of the number of excursions into the escapeenclosure.

Thus, following the administration of 100 mg/Kg/p.o. of the compounds ofCode Nos. 72 457 and 72 736, an augmentation of 30% in the number ofexcursions in the escape test, is observed.

11. Antiarythmic properties

Administered by intraperitoneal means, the compounds of formula (I) arecapable of protecting the mouse against the ventricular fibrillationsprovoked by the inhalation of chloroform.

By way of example, the compounds of Code Nos. 72 488, 72 568 and 72 479present a DE 50 of 200 mg/Kg/i.p.

12. Diuretic properties

The compounds of formula (I), administered by oral means to the mouse,simultaneously with a volume of 1 ml. of an isotonic solution of sodiumchloride per 25 g of the corporeal weight of the mouse, are capable ofprovoking an augmentation of the volume of urine emitted by reference tocontrol animals, the volume being measured for 6 hours followingadministration.

By way of example, the following Table XI lists the results obtained bythe administration of 25 mg/Kg/p.o. of different compounds of formula(I).

                  TABLE XI                                                        ______________________________________                                        Code No. of    Percentage augmentation                                        compound tested                                                                              of urinary elimination (%)                                     ______________________________________                                        72 447         70                                                             72 603         45                                                             72 457         45                                                             72 692         70                                                             ______________________________________                                    

13. Antihistaminic properties

The compounds of formula I, introduced in the conserving medium, arecapable of opposing the contractural action of histamine on the isolatedileum of the guinea-pig. This activity is evaluated by takingpromethazine as standard.

By way of example, the compound of Code No. 72 366 presents anequivalent activity to that of promethazine.

As a result of a comparison between the pharmacologically active dosesmentioned above and the lethal doses listed in the following Table XII,the difference between said doses is sufficiently great to permit theutilisation of the compounds of formula (I) in therapeutics.

                  TABLE XII                                                       ______________________________________                                        Code No. of Dose administered                                                                            Percentage                                         compound tested                                                                           (mg/Kg/p.o.)   mortality (%)                                      ______________________________________                                        72 491      2 000          0                                                  72 493      2 200          ≃5                                   72 573      1 250          ≃50                                  72 494      2 000          0                                                  72 464      2 000          0                                                  72 523      2 000          0                                                  72 412      2 000          0                                                  72 414      1 800          ≃50                                  72 525      2 000          ≃10                                  72 534      2 000          0                                                  72 377      2 000          0                                                  72 391      2 000          0                                                  72 398      2 000          0                                                  72 490      1 800          ≃50                                  72 617      2 600          ≃50                                  72 487      1 825          ≃50                                  72 488      2 000          0                                                  72 526      1 400          ≃50                                  72 568      1 425          ≃50                                  72 663      1 800          ≃50                                  72 447      2 000          0                                                  72 540      2 000          0                                                  72 603      2 000          0                                                  72 359      2 000          0                                                  72 366      2 000          0                                                  72 712      2 000          0                                                  72 708      1 600          ≃50                                  72 390      2 000          0                                                  72 479      2 000          0                                                  72 457      2 000          0                                                  72 478      2 000          0                                                  72 574      2 200          ≃50                                  72 692      1 400          ≃50                                  72 736      2 000          ≃10                                  72 727      2 000          O                                                  ______________________________________                                    

The compounds of formula (I) are useful in the treatment ofgastro-duodenal ulcers, visceral spasms, asthma, anxiety, nervousness,painful inflammations, diverse originating pains, circulatoryinsufficiencies, cardiac arythmies, hypertension, oedemas, allergies andasthenia.

They may be administered by oral means in the form of tablets, gelulesand dragees containing 10 to 400 mg of active ingredient (1 to 6 timesper day), or suspensions containing 0.5 to 5% of active ingredient (1 to6 spoonfuls per day), by parenteral means in the form of injectableampoules containing 5 to 50 mg of active ingredient (1 to 3 times perday) and by rectal means in the form of suppositories containing 10 to200 mg of active ingredient (1 to 3 times per day).

Accordingly, the present invention also relates to a therapeuticcomposition comprising a compound of the general formula (I) togetherwith a therapeutically acceptable carrier.

What we claim is:
 1. A compound having the formula ##EQU9## wherein Aris phenyl or phenyl substituted by one halogen, or one or two alkylhaving 1 to 4 carbon atoms, or one, two or three alkoxy having 1 to 4carbon atoms, and R₁ and R₂ each is alkyl having one to 4 carbon atomsor ##EQU10## is piperidino, pyrrolidino, morpholino orhexamethyleneimino, and the pharmacologically acceptable acid additionsalts thereof.
 2. A compound as claimed in claim 1, in which Ar isphenyl.
 3. A compound as claimed in claim 1, in which Ar isp-chlorophenyl or p-fluorophenyl.
 4. A compound as claimed in claim 1,in which Ar is p-tolyl or 2,4-dimethyl phenyl.
 5. A compound as claimedin claim 1, in which Ar is p-(n-butoxy)phenyl, 2,4-dimethoxyphenyl or3,4,5-trimethoxyphenyl.
 6. A compound as claimed in claim 1 in which##EQU11## is dimethylamino, diethylamino, pyrrolidino, piperidino,morpholino or hexamethyleneimino.
 7. A compound as claimed in claim 1,in which Ar is 2,4-dimethylphenyl and ##EQU12## is piperidino.